# Development of a whole heart model of the J wave syndromes and novel approaches to pharmacologic management of associated life-threatening arrhythmias

> **NIH NIH R01** · LANKENAU INSTITUTE FOR MEDICAL RESEARCH · 2021 · $629,459

## Abstract

The J-wave syndromes (JWSs), consisting of the Brugada (BrS) and Early Repolarization Syndromes (ERS), have presented
a challenge to the cardiology community for over two decades. JWSs are inherited cardiac arrhythmia and sudden cardiac
death syndromes that share ECG features, clinical outcomes, and risk factors, as well as a common arrhythmic platform
related to amplification of the J wave of the ECG. Two principle hypotheses have been proposed to underlie BrS:
repolarization and depolarization. The principal aim of this proposal is to develop a whole heart model of BrS and ERS to
advance our understanding of the pathophysiology of these syndromes. We will pharmacologically mimic the genetic
defects known to underlie the JWSs and record a 12 lead ECG, unipolar and bipolar transmural electrograms from the right
ventricular outflow tract (RVOT), RV apex and Left Ventricular inferior wall of Langendorff-perfused whole-hearts. A
critical and unique feature will be the use of floating glass microelectrodes to record transmembrane action potentials from
the epicardial surface of the RVOT of the intact heart. This aim will, for the first time, provide a whole heart model of the
JWSs capable of a direct test of the two hypotheses and definitive identification of the substrate and triggers responsible for
the development of ventricular tachycardia and fibrillation (VT/VF). Although implantation of a cardioverter defibrillator
(ICD) is generally accepted as first-line therapy for symptomatic JWS patients, a pharmacological approach to therapy is
recommended in cases of electrical storm, as an adjunct to ICD, and as preventative therapy for asymptomatic patients at
risk for arrhythmic events. A secondary aim of this proposal is to identify safe an effective pharmacologic approaches to
therapy of these life-threatening syndromes. We will determine structure-activity relationships (SAR) for acacetin and a test
set of structurally similar congeners capable of selectively inhibiting Ito, thus acting to prevent or suppress
arrhythmogenicity. We will determine the potency and efficacy of the congeners for inhibition of Ito in HEK cells expressing
wild type (WT) Kv4.3 and KCNIP2 as well as pathology-mediated augmentation of Ito using polycistronic constructs that
include WT and mutant SCN5A and KCND3 genes that have been associated with the JWSs. We will determine the
selectivity of these agents in canine and human ventricular cardiomyocytes. We will then promote the most promising
compound(s) to studies in canine coronary-perfused wedge preparations and, ultimately in Langendorff-perfused canine
whole-heart models of BrS and ERS. Successful completion of these specific aims should importantly advance our
understanding of the cellular mechanisms involved in the pathogenesis of the JWSs and provide a major advance
in the pharmacological approach to therapy. These studies have the potential to provide the first major
breakthrough in over 20 years for identification...

## Key facts

- **NIH application ID:** 10126055
- **Project number:** 5R01HL152201-02
- **Recipient organization:** LANKENAU INSTITUTE FOR MEDICAL RESEARCH
- **Principal Investigator:** Charles Antzelevitch
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $629,459
- **Award type:** 5
- **Project period:** 2020-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10126055

## Citation

> US National Institutes of Health, RePORTER application 10126055, Development of a whole heart model of the J wave syndromes and novel approaches to pharmacologic management of associated life-threatening arrhythmias (5R01HL152201-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10126055. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*