# Engineered Human Heart Slice for Testing Drug-Induced Arrhythmia

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2021 · $708,613

## Abstract

New standards are under development for cardiac safety testing of drugs for risk of arrhythmia, ultimately
with the preclinical goal of predicting risk for Torsade de Pointes (TdP). In the U.S. the Comprehensive in vitro
Proarrhythmia Assay (CiPA) initiative has been advocated by government regulatory agencies, public-private
partnerships, industry and academia. One component of the initiative rests on the usage of human induced
pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) as a validation platform of drug responses that can
replace heterologous expression systems which dwell on block of a single ion channel (HERG). If adopted by the
FDA, CiPA represents a major step forward for drug testing using cells that contain the major ion channels and
signaling pathways found in human heart. This application of hiPSC-CMs is an area of active research and
development, and numerous contract research organizations and most pharmaceutical companies have founded
labs to perform high throughput screening of test compounds using these cells. However, current hiPSC-CM
screens tend to be on single or small numbers of cells that exhibit immaturity and heterogeneity. In addition,
arrhythmic events are limited to early afterdepolarizations (EADs) or irregular beating. TdP is ultimately a
multicellular tissue phenomenon that results from reentrant or multifocal ectopic activity that require a minimum
size to be revealed.
 The goal of this project is to develop an in vitro model suitable for testing pharmacological compounds and
assessing risk for tissue-level arrhythmia. Three research labs at Hopkins will contribute their expertise for the
project. The tissue platform used to support the hiPSC-CMs will be the Engineered Heart Slice developed in Tung’s
cardiac electrophysiology lab. Version 2.0 of the slice with improved physiological function will be implemented
using proven and putative maturation stimulants, and then used to test for drug-induced reentrant or multifocal
arrhythmia. To this end, metabolic maturation of the cells will be pursued via the expertise of the Boheler lab,
which has identified CD36 as a cell surface marker distinguishing cells that are metabolically more mature. A
bioinformatics approach developed in Kwon’s cardiac developmental biology lab will be used to follow the
maturation trajectory of the cardiomyocytes. The convergence of these technologies will result in an advanced in
vitro tissue model that will be used to independently and mechanistically assess the proarrhythmic effects of
selected compounds which have been identified clinically as low, intermediate, and high risk, and to determine
whether the maturation state of the cardiomyocytes affects their drug responses. This approach represents a new
paradigm for cardiac safety testing – one that is a step closer to predicting TdP-like arrhythmic events in the
myocardium – and may establish new standards for the utility, validity, and maturation-dependence of hiPSC-CMs
as an ...

## Key facts

- **NIH application ID:** 10126056
- **Project number:** 5R01HL152249-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** LESLIE TUNG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $708,613
- **Award type:** 5
- **Project period:** 2020-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10126056

## Citation

> US National Institutes of Health, RePORTER application 10126056, Engineered Human Heart Slice for Testing Drug-Induced Arrhythmia (5R01HL152249-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10126056. Licensed CC0.

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