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Schwartz, P. J.

Publications and source records attributed to Schwartz, P. J..

2 recordsLinked to original sources

Batch Action PoTential Analyser (BAPTA): an open source tool for automated high throughput analysis of cardiac action potentials

The cardiac action potential (AP) is a key species-specific feature of cardiomyocytes that occurs in response to coordinated actions of ion channels. It represents the first step of the cardiac excitation-contraction coupling and it is crucial for cardiomyocyte (CM) physiology. Changes in the cardiac AP may primarily occur as a consequence of diseases or as a direct or unwanted response to drugs. Our ability to quantify these changes defines the reliability of our measurements and its throughput. Cardiac AP parameters are often quantified through manual time-consuming data analysis protocols or custom-made and proprietary data analysis pipelines; to the best of our knowledge, no tools are currently available for automated cardiac AP analysis and AP parameter quantification. Here we introduce a free and open source software tool named Batch Action PoTential Analyser (BAPTA), written in the R language, designed to i) overcome the inherent operator-dependent bias on trace selection affecting reproducibility, ii) vastly improve the throughput of the analyses of large datasets and iii) analyse both spontaneous and triggered APs from CMs of multiple species and origin. We present here four use-cases in which BAPTA can be used at high throughput to investigate the effects of: 1) a disease (cardiomyopathy) on rat CMs, 2) drugs on mouse pacemaker cells, 3) rate-dependency of AP duration in guinea pig CMs and 4) metabolic electrophysiological maturation in human stem-cell-derived CMs. Overall, BAPTA consistently provides faster, more reproducible and scalable readouts which excellently correlate with manual analyses performed by experienced electrophysiologists.

physiology↗

Use of hiPSC-derived cardiomyocytes to rule out proarrhythmic effects of drugs: the case of hydroxychloroquine in COVID-19

In the early phases of the COVID-19 pandemic, drug repurposing was widely used to identify compounds that could improve the prognosis of symptomatic patients infected by SARS-CoV-2. Hydroxychloroquine (HCQ) was one of the first drugs used to treat COVID-19 patients due to its supposed capacity of inhibiting SARS-CoV-2 infection and replication in vitro. While its efficacy is debated, HCQ has been associated with QT interval prolongation and potentially Torsades de Pointes, especially in patients predisposed to developing drug-induced Long QT Syndrome (LQTS) as silent carriers of variants associated with congenital LQTS. If confirmed, these effects represent a limitation to the at-home use of HCQ for COVID-19 infection as adequate ECG monitoring may be challenging. We investigated the proarrhythmic profile of HCQ with Multi-Electrode Arrays after subchronic exposure of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from two healthy donors, one asymptomatic and two symptomatic LQTS patients. We demonstrate that: I) HCQ induced a concentration-dependent Field Potential Duration (FPD) prolongation in vitro and triggered arrhythmias that halted the beating at high concentration. II) hiPSC-CMs from healthy or asymptomatic carriers tolerated higher concentrations of HCQ and showed lower susceptibility to HCQ-induced electrical abnormalities regardless of baseline FPD values. These findings agree with the clinical safety records of HCQ and demonstrated that hiPSC-CMs potentially discriminates symptomatic vs asymptomatic mutation carriers through pharmacological interventions. Disease-specific cohorts of hiPSC-CMs may be a valid preliminary addition to quickly assess drug safety in vulnerable populations, offering rapid preclinical results with valuable translational relevance for precision medicine.

physiology↗