Electrical impedance-based contractile stress measurement of human iPSC-Cardiomyocytes

Abstract

Heart failure fundamentally results from loss of cardio myocyte contractility. Developing new methods that quantify the contractile stress of the human cardiomyocyte would facilitate the study of the molecular mechanism of heart failure and advance therapy development, to improve the current five year survival for these patients. The measurement of cellular electrical impedance measurement was recently applied to monitor cardiomyocyte beating rate and rhythm, for the study at cellular maturation, and for drug screening. However, due to the lack of a quantified relationship between the impedance signal and contractile stress, change of cardiomyocyte contractile stress cannot genuinely be quantified from impedance measurements. Here, we report the first quantitative relationship between contractile stress and impedance, which enables the accurate prediction of cardiomyocyte contractility using impedance signals. Through simultaneous measurement of beating human iPSC-cardiomyocytes using impedance spectroscopy and atomic force microscopy, a power-law relationship between impedance and contractile stress was established with a confidence level of 95%. The quantitative relationship was validated using pharmacology known to alter cardiomyocyte contractility and beating (verapamil, using clinically relevant concentrations of 0.05 μM, 0.10 μM, and 0.15 μM). The contractile stress values as measured by AFM were 9.04 ± 0.14 kPa (0.05 μM), 7.72 ± 0.11 kPa (0.10 μM) and 6.23 ± 0.17 kPa (0.15 μM), and as predicted by impedance using the derived power-law relationship were 9.39 kPa, 7.76 kPa, and 6.05 kPa with a relative error of 3.73%. Our power-law relationship is the first to describe a quantitative correlation between contractile stress and impedance, broadening the application of electrical impedance measurement for characterizing complex cardiac functions (beating rate, beating rhythm and contractile stress).

Keywords: Atomic force microscopy; Contractile stress; Electrical impedance; Human iPSC-Cardiomyocytes; Mechanotransduction.