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

Oleg E. Osadchii

doi:10.1371/journal.pone.0191514

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

Oleg E. Osadchii

Department of Biomedical Sciences

1 Citation (Scopus)

28 Downloads (Pure)

Abstract

Non-uniform shortening of the action potential duration (APD(90)) in different myocardial regions upon heart rate acceleration can set abnormal repolarization gradients and promote arrhythmia. This study examined whether spatial heterogeneities in APD(90) 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 APD(90) 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 APD(90) 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 APD(90) 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 APD(90) 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 APD(90) restitution, which can be indirectly determined through ECG assessments of the JTend vs. JTpeak dynamics at variable pacing rates.

Original language	English
Article number	e0191514
Journal	PLoS ONE
Volume	13
Issue number	1
Number of pages	20
ISSN	1932-6203
DOIs	https://doi.org/10.1371/journal.pone.0191514
Publication status	Published - Jan 2018

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@article{9e8203e655064b388130b611dea4e5c4,

title = "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 (APD(90)) in different myocardial regions upon heart rate acceleration can set abnormal repolarization gradients and promote arrhythmia. This study examined whether spatial heterogeneities in APD(90) 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 APD(90) 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 APD(90) 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 APD(90) 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 APD(90) 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 APD(90) restitution, which can be indirectly determined through ECG assessments of the JTend vs. JTpeak dynamics at variable pacing rates.",

author = "Osadchii, {Oleg E.}",

year = "2018",

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T1 - Arrhythmogenic drugs can amplify spatial heterogeneities in the electrical restitution in perfused guinea-pig heart

T2 - An evidence from assessments of monophasic action potential durations and JT intervals

AU - Osadchii, Oleg E.

PY - 2018/1

Y1 - 2018/1

N2 - Non-uniform shortening of the action potential duration (APD(90)) in different myocardial regions upon heart rate acceleration can set abnormal repolarization gradients and promote arrhythmia. This study examined whether spatial heterogeneities in APD(90) 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 APD(90) 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 APD(90) 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 APD(90) 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 APD(90) 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 APD(90) restitution, which can be indirectly determined through ECG assessments of the JTend vs. JTpeak dynamics at variable pacing rates.

AB - Non-uniform shortening of the action potential duration (APD(90)) in different myocardial regions upon heart rate acceleration can set abnormal repolarization gradients and promote arrhythmia. This study examined whether spatial heterogeneities in APD(90) 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 APD(90) 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 APD(90) 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 APD(90) 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 APD(90) 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 APD(90) restitution, which can be indirectly determined through ECG assessments of the JTend vs. JTpeak dynamics at variable pacing rates.

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DO - 10.1371/journal.pone.0191514

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C2 - 29352276

SN - 1932-6203

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