We study the autonomous motion of catalytic nanorods in Gibbs monolayers. The catalytic activity of the rods on a hydrogen peroxide aqueous subphase gives rise to anomalous translational and rotational diffusion. The rods perform a Levy-walk superdiffusive motion that can be decomposed into thermal orientation fluctuations and an active motion of the rods with a constant velocity along their long axis. Since interfacial dissipation increases relative to bulk phase dissipation when miniaturizing the size of objects moving in the interface, the autonomous nanorods allow for precise measurements of surface shear viscosities as low as a few nN s/m. The cross over from active motion toward passive diffusion when increasing the surfactant concentration is explained by a loss of friction asymmetry of the rods.
1236 Cellular and molecular electrophysiology tural heart disease but also associated with atrial fibrillation, ventricular tachycardia and sudden cardiac death. Several mutations in genes encoding sarcomeric proteins were identified to cause hypertrophy and diastolic dysfunction. However, it remains widely unclear how those mutations can promote arrhythmias. Purpose: The goal of this study was to elucidate the functional role of a novel mutation in human induced-pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs) compared to an isogenic control and a control cell line of a healthy donor. Methods and results: DNA sequencing of a panel of 19 cardiac genes identified a unique ACTN2 c.740C>T transition (p.Thr247Met; actin-binding domain) in an HCM patient with left ventricular hypertrophy, outflow obstruction and atrial fibrillation. This ACTN2 variant encoding a-Actinin-2 was also found in the HCM-affected son of the index patient, but not in the ExAc population. Skin fibroblasts from the HCM patient and a healthy donor (CTR) were reprogrammed into hiPSCs and further differentiated into CMs. We repaired the mutation in the HCM hiPSC with the CRISPR/Cas9 gene editing system (isogenic CTR). In 2D-culture CMs showed 4.9-fold higher cell areas in HCM than CTR. 3D-engineered heart tissues (EHTs) generated from hiPSC CMs showed no differences in peak force, but longer relaxation time in HCM than CTR. Action potentials (AP) were measured with sharp microelectrodes in intact EHTs paced between 0.5 and 3 Hz in the presence of ivabradine. AP duration (APD) was markedly longer over all frequencies in HCM than in isogenic CTR or CTR (APD90 at 1 Hz: 408±7 ms, n=24; 212±22 ms, n=4; 236±8 ms, n=24; p<0.001). The prolonged APD in HCM EHTs was in line with the slightly prolonged QTc interval in the index patient (448 ms) and her son (471 ms). Preliminary evaluation revealed higher CACNA1C (ICa) and lower KCNH2 (IKr) mRNA levels in HCM than CTR EHTs, which might contribute to AP prolongation. To evaluate the repolarisation reserve, we added E-4031 (IKr inhibitor) and found it prolonged APs stronger in HCM EHTs than CTR. At E-4031 concentrations of >100 nM, HCM EHTs showed spontaneous depolarisations despite the use of ivabradine (normally blocking spontaneous depolarization in EHTs), while CTR did not. Conclusion:The novel ACTN2 mutation is likely HCM-causing. In hiPSC-CM, the mutation in ACTN2 was associated with pronounced hypertrophy, AP prolongation and a marked APD-prolongation upon to IKr block accompanied with automaticity. These results suggest a primary long QT-like phenotype caused by this novel ACTN2 mutation in a family of HCM and suggest special caution in treating these patients with QT prolonging drugs.
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