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

Award Number: R01HL152201
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2020
PERIOD OF PERFORMANCE END DATE: 03/31/2024

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Development of a whole heart model of the J wave syndromes and novel approaches to pharmacologic management of associated life-threatening arrhythmias - 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 of safe and effective agent(s) for JWS. Equally important, the data generated will provide a unique platform for further development of novel therapies via the identification of efficacious lead compounds. Successful management of these syndromes, for which treatment alternatives are currently very limited, will close a very significant gap in our therapeutic armamentarium for individuals at risk for sudden cardiac death.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2023 ( Subtotal = $629,459 )
2023	2023	LANKENAU INSTITUTE FOR MEDICAL RESEARCH	100 E LANCASTER AVE	WYNNEWOOD	PA	19096	MONTGOMERY	USA	Cardiovascular Diseases Research	000	4	3/13/2023	NON-COMPETING CONTINUATION	$629,459
														Subtotal = $629,459

Issue Date FY: 2022 ( Subtotal = $629,459 )
2022	2022	LANKENAU INSTITUTE FOR MEDICAL RESEARCH	100 E LANCASTER AVE	WYNNEWOOD	PA	19096	MONTGOMERY	USA	Cardiovascular Diseases Research	000	3	6/17/2022	NON-COMPETING CONTINUATION	$629,459
														Subtotal = $629,459

Issue Date FY: 2021 ( Subtotal = $629,459 )
2021	2021	LANKENAU INSTITUTE FOR MEDICAL RESEARCH	100 E LANCASTER AVE	WYNNEWOOD	PA	19096	MONTGOMERY	USA	Cardiovascular Diseases Research	000	2	3/29/2021	NON-COMPETING CONTINUATION	$629,459
														Subtotal = $629,459

Issue Date FY: 2020 ( Subtotal = $629,459 )
2020	2020	LANKENAU INSTITUTE FOR MEDICAL RESEARCH	100 E LANCASTER AVE	WYNNEWOOD	PA	19096	MONTGOMERY	USA	Cardiovascular Diseases Research	000	1	3/11/2020	NEW	$629,459
2020	2020	LANKENAU INSTITUTE FOR MEDICAL RESEARCH	100 E LANCASTER AVE	WYNNEWOOD	PA	19096	MONTGOMERY	USA	Cardiovascular Diseases Research	001	1	7/2/2020	NEW	$0
														Subtotal = $629,459

Grand Total All Awards = $2,517,836

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

Award Number: R01HL152201

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/01/2020

PERIOD OF PERFORMANCE END DATE: 03/31/2024

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