Arrhythmogenic drugs can amplify spatial heterogeneities in the electrical restitution in perfused guinea-pig heart: An evidence from assessments of monophasic action potential durations and JT intervals

Abstract

Non-uniform shortening of the action potential duration (APD90) in different myocardial regions upon heart rate acceleration can set abnormal repolarization gradients and promote arrhythmia. This study examined whether spatial heterogeneities in APD90 restitution can be amplified by drugs with clinically proved proarrhythmic potential (dofetilide, quinidine, procainamide, and flecainide) and, if so, whether these effects can translate to the appropriate changes of the ECG metrics of ventricular repolarization, such as JT intervals. In isolated, perfused guinea-pig heart preparations, monophasic action potentials and volume-conducted ECG were recorded at progressively increased pacing rates. The APD90 measured at distinct ventricular sites, as well as the JTpeak and JTend values were plotted as a function of preceding diastolic interval, and the maximum slopes of the restitution curves were determined at baseline and upon drug administration. Dofetilide, quinidine, and procainamide reverse rate-dependently prolonged APD90 and steepened the restitution curve, with effects being greater at the endocardium than epicardium, and in the right ventricular (RV) vs. the left ventricular (LV) chamber. The restitution slope was increased to a greater extent for the JTend vs. the JTpeak interval. In contrast, flecainide reduced the APD90 restitution slope at LV epicardium without producing effect at LV endocardium and RV epicardium, and reduced the JTpeak restitution slope without changing the JTend restitution. Nevertheless, with all agents, these effects translated to the amplified epicardial-to-endocardial and the LV-to-RV non-uniformities in APD90 restitution, paralleled by the increased JTend vs. JTpeak difference in the restitution slope. In summary, these findings suggest that arrhythmic drug profiles are partly attributable to the accentuated regional heterogeneities in APD90 restitution, which can be indirectly determined through ECG assessments of the JTend vs. JTpeak dynamics at variable pacing rates.

Cardiac transmembrane ion channels and action potentials: cellular physiology and arrhythmogenic behavior

“…In these dogs, the APD prolongation was larger in the left ventricle than in the right ventricle (647). The opposite was observed in guinea pigs, i.e., the APDprolonging drugs dofetilide and quinidine lengthened APD more in the right ventricle (651). These findings highlight important differences among species in their responses to drugs with repolarization-prolonging effects.…”

Transient outward K+ current can strongly modulate action potential duration and initiate alternans in the human atrium

“…K ϩ CHANNEL ISOFORMS REGULATE HUMAN ATRIAL ARRHYTHMOGENESIS current and associated details of atrial refractoriness (18,48,88,125) or on whether the K ϩ channels that underlie I to are predominantly Kv1.4 or Kv4.3 (cf. 85,121).…”

“…If so, it is important to recognize that when Kv1.4 is the predominant drug "target," it can confer new electrophysiological properties to the atrial substrate (2,10,23,48,63,71,80,85). Moreover, the spatial heterogeneity of the electrophysiological properties in mammalian atria (right vs. left atrium, right atrium vs. atrial septum) will need to be accounted for (36,39,86) since it is known that any significant differences in spatial localized APD within the atrial syncytium can influence arrhythmogenesis (88,96,114).…”

Electroanatomical Adaptations in the Guinea Pig Heart from Neonatal to Adulthood

“…Epicardial APD heterogeneity was also more prominent during slower versus faster pacing rates. Prior studies have reported regional heterogeneity between the left versus right ventricle 75 using isolated ventricular cardiomyocytes, and/or base versus apex 46 in intact heart preparations from young guinea pigs. Although, in our study, regional heterogeneity was largely absent in adult animals ( Figure 5C , Figure 7D-E ).…”