Concordance of cardiovascular contractility between FLEXcyte assay and the rat left ventricular catheterized telemetry model

Abstract

Changes in cardiac contractility can lead to hemodynamic alterations and abnormal structural changes within the heart, which over time can cause reduced function and failure. Recent advancements in technology, allowing the assessment of cardiac contractility to become easier and more efficient, have resulted in a greater focus on contractility measures within safety pharmacology studies. In particular, the development of in vitro assays such as the FLEXcyte assay, which utilizes human stem cell derived cardiomyocytes (hiPSC-CMs), allows for the ability to screen for potential contractility changes earlier in development. The objective of this study was to explore the concordance of changes in contractility between FLEXcyte measurements and left ventricular pressure measurements (LV + dP/dt_max) in the telemetered rat model. Verapamil and milrinone were selected as tool compounds. For the FLEXcyte, hiPSC-CMs (Cardiosight-S; NEXCEL Co., Ltd.) were maintained in a serum-free culture medium for 7 days with media changes every 48 h. Initially, 30 s of baseline was recorded every 15 min for 1 h. Following baseline, a dose response curve was attained using 5 concentrations. Spontaneous beat rate and contraction amplitude were analyzed to determine the concordance with heart rate and LV + dP/dt_max in the telemetered rat. For the telemetered study, CRL WI(Han) rats were instrumented with HD-S21 (DSI) implants monitoring systemic and LV pressures and placed into a 4 × 4 latin square design for each tool compound. For verapamil, the FLEXcyte showed an increase in beat rate (22.7 % at 33 nM) and a substantial decrease in amplitude (66.5 % at 33 nM), which concords well with the increase in heart rate (25.2 %) and decrease in LV + dP/dt_max (−33.6 %) in the telemetered rat. However, for milrinone, the FLEXcyte did not show any significant changes in beat rate or amplitude while the telemetered rat showed increases in both heart rate (up to 57 %) and LV + dP/dt_max (up to 87.4 %). While more work is needed, this data highlights the importance of conducting both in vitro and in vivo studies to assess the potential effects on cardiac contractility in drug development, allowing for the identification of molecules with diverse mechanisms of action.