The development of L-type Ca2+ current mediated alternans does not depend on the restitution slope in canine ventricular myocardium

Noémi Tóth,Gergő Bitay,Norbert Nagy,András Varró,Julius Gy Papp,Jozefina Szlovák,Balázs Horváth,Zsófia Kohajda,Roland Veress

doi:10.1038/s41598-021-95299-7

Noémi Tóth, Gergő Bitay + Show 7 more

Open Access

https://doi.org/10.1038/s41598-021-95299-7

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Journal: Scientific Reports	Publication Date: Aug 17, 2021
Citations: 1	License type: open-access

Affiliation: University of Szeged, University of Debrecen

Abstract

Cardiac alternans have crucial importance in the onset of ventricular fibrillation. The early explanation for alternans development was the voltage-driven mechanism, where the action potential (AP) restitution steepness was considered as crucial determining factor. Recent results suggest that restitution slope is an inadequate predictor for alternans development, but several studies still claim the role of membrane potential as underlying mechanism of alternans. These controversial data indicate that the relationship of restitution and alternans development is not completely understood. APs were measured by conventional microelectrode technique from canine right ventricular papillary muscles. Ionic currents combined with fluorescent measurements were recorded by patch-clamp technique. APs combined with fluorescent measurements were monitored by sharp microelectrodes. Rapid pacing evoked restitution-independent AP duration (APD) alternans. When non-alternating AP voltage command was used, Ca2+i-transient (CaT) alternans were not observed. When alternating rectangular voltage pulses were applied, CaT alternans were proportional to ICaL amplitude alternans. Selective ICaL inhibition did not influence the fast phase of APD restitution. In this study we found that ICaL has minor contribution in shaping the fast phase of restitution curve suggesting that ICaL—if it plays important role in the alternans mechanism—could be an additional factor that attenuates the reliability of APD restitution slope to predict alternans.

Highlights

Cardiac alternans refer to a regular beat-to-beat oscillation of the ECG T-waves caused by parallel alternans of the action potential (AP) and the CaT at the cellular level[1,2]
A general view is that the voltage-driven alternans are governed by the restitution slope, i.e. alternans are expected to develop when the slope of AP duration-diastolic interval (APD-Diastolic intervals (DI)) function is larger than 117
Alternans could be evoked in all cases (n = 20) with clear threshold, i.e. when the pacing length became equal or shorter than 250 ms

Summary

Introduction

Cardiac alternans refer to a regular beat-to-beat oscillation of the ECG T-waves caused by parallel alternans of the AP and the CaT at the cellular level[1,2]. A general view is that the voltage-driven alternans are governed by the restitution slope, i.e. alternans are expected to develop when the slope of AP duration-diastolic interval (APD-DI) function is larger than 117 This means that restitution-hypothesis—which was originally proposed by Nolasco and D ahlen17—represents an ultimate underlying factor of the voltage-driven a lternans[1,5,7]. The restitution hypothesis was challenged by several laboratories[1,18], at the same time there are experimental and modeling papers claiming important role of membrane voltage in the development of a lternans[19,20,21,22] This discrepancy suggests that the relationship of restitution and alternans is not completely understood and requires further investigations

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