Automated Patch-Clamp and Induced Pluripotent Stem Cell-Derived Cardiomyocytes: A Synergistic Approach in the Study of Brugada Syndrome

Abstract

The development of high-throughput automated patch-clamp technology is a recent breakthrough in the field of Brugada syndrome research. Brugada syndrome is a heart disorder marked by abnormal electrocardiographic readings and an elevated risk of sudden cardiac death due to arrhythmias. Various experimental models, developed either in animals, cell lines, human tissue or computational simulation, play a crucial role in advancing our understanding of this condition, and developing effective treatments. In the perspective of the pathophysiological role of ion channels and their pharmacology, automated patch-clamp involves a robotic system that enables the simultaneous recording of electrical activity from multiple single cells at once, greatly improving the speed and efficiency of data collection. By combining this approach with the use of patient-derived cardiomyocytes, researchers are gaining a more comprehensive view of the underlying mechanisms of heart disease. This has led to the development of more effective treatments for those affected by cardiovascular conditions.

Development of automated patch clamp assays to overcome the burden of variants of uncertain significance in inheritable arrhythmia syndromes

“…In addition to increasing throughput, APC offer many advantages including cell handling facilities, ability to clamp current or voltage, temperature control which is important for temperature-dependent channels and compounds, and internal solution exchange that enables activation or inhibition by compounds added intracellularly. Furthermore, APC is applicable to various cell expression systems used in cardiac electrophysiology experiments ( Table 1 ), including human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) ( Ma et al, 2011 ; Becker et al, 2013 ; Obergrussberger et al, 2016 ; Rajamohan et al, 2016 ; Li et al, 2019 ; Potet et al, 2020 ; Rapedius et al, 2022 ; Melgari et al, 2023 ). There are, however, some limitations.…”

The Action Potential Clamp Technique as a Tool for Risk Stratification of Sinus Bradycardia Due to Loss-of-Function Mutations in HCN4: An In Silico Exploration Based on In Vitro and In Vivo Data

“…The patch clamp technique is a >40-year-old electrophysiological tool [ 28 ] and is considered the gold standard in electrophysiology because of its ability to measure both action potentials (APs) and specific membrane currents, and even single-channel currents, in detail [ 29 ]. Functional consequences of variations in genes encoding cardiac ion channels (for reviews, see Marbán [ 30 ], Schwartz et al [ 10 ], and Wilde et al [ 15 ]) can be studied in a large variety of models, such as isolated cells from genetically modified animals [ 31 , 32 , 33 ] and human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) [ 34 , 35 , 36 ]. However, mammalian cell lines in which the wild-type and the variant cDNA of a given ion channel can be expressed are still widely used to study the functional properties of ion currents [ 37 , 38 ].…”