Intermittent optogenetic tachypacing of atrial engineered heart tissue induces only limited electrical remodelling.

Abstract:

ABSTRACT:Atrial tachypacing is an accepted model for atrial fibrillation (AF) in large animals and in cellular models. Human induced pluripotent stem cells derived cardiomyocytes (hiPSC-CM) provide a novel, human source to model cardiovascular diseases. Here we investigated whether optogenetic tachypacing of atrial-like hiPSC-CMs grown into engineered heart tissue (aEHT) can induce AF-remodeling.After differentiation of atrial-like cardiomyocytes from hiPSCs using retinoic acid, aEHTs were generated from ∼1 million atrial-like hiPSC-CMs per aEHT. AEHTs were transduced with lentivirus expressing channelrhodopsin-2 to enable optogenetic stimulation by blue light pulses. AEHTs underwent optical tachypacing at 5 Hz for 15 s twice a minute over three weeks and compared to transduced spontaneously beating isogenic aEHTs (1.95±0.07 Hz). Force and action potential duration did not differ between spontaneously beating and tachypaced aEHTs. Action potentials in tachypaced aEHTs showed higher upstroke velocity (138±15 V/s vs. 87±11 V/s, n=15-13/3; p=0.018), possibly corresponding to a tendency for more negative diastolic potentials (73.0±1.8 mV vs. 68.0±1.9 mV; p=0.07). Tachypaced aEHTs exhibited a more irregular spontaneous beating pattern (beat-to-beat scatter: 0.07±0.01 vs. 0.03±0.004 s, n=15-13/3; p=0.008). Targeted expression analysis showed higher RNA levels of KCNJ12 (Kir2.2, inward rectifier (IK1); 69±7 vs. 44±4, p=0.014) and NPPB (NT-proBNP; 39690±4834 vs. 23671±3691; p=0.024).Intermittent tachypacing in aEHTs induces some electrical alterations found in AF and induces an arrhythmic spontaneous beating pattern, but does not affect resting force. Further studies using longer, continuous, or more aggressive stimulation might clarify the contribution of different rate patterns on the changes in aEHT mimicking the remodeling process from paroxysmal to persistent atrial fibrillation.

journal_name

J Cardiovasc Pharmacol

authors

Lemoine MD,Lemme M,Ulmer BM,Braren I,Krasemann S,Hansen A,Kirchhof P,Meyer C,Eschenhagen T,Christ T

doi

10.1097/FJC.0000000000000951

subject

Has Abstract

pub_date

2020-12-22 00:00:00

eissn

0160-2446

issn

1533-4023

pii

00005344-900000000-98307

journal_volume

Publish Ahead of Print

pub_type

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