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Novel Approaches to Pharmacologic Management of Life-Threatening Arrhythmias Associated with the J Wave Syndromes

Award Number: R56HL138103
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2018
PERIOD OF PERFORMANCE END DATE: 08/31/2020

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Novel Approaches to Pharmacologic Management of Life-Threatening Arrhythmias Associated with the J Wave Syndromes - Project Summary Abstract Brugada syndrome (BrS) and early repolarization syndrome (ERS) are inherited cardiac arrhythmia syndromes that contribute to sudden cardiac death of young adults as they reach the prime of their lives. In some cases these syndromes have been shown to be responsible for sudden infant death syndrome. They share similar ECG features, clinical outcomes, risk factors, as well as the development of prominent J waves. The cellular mechanisms underlying the development of ventricular tachycardia and fibrillation (VT/VF) associated with these two channelopathies, and the mechanisms of action of drug therapies, remain a matter of debate. A principal aim of our proposal is to advance the understanding of the cellular and ionic basis for BrS and ERS, and determine the effectiveness and cellular basis for the ameliorative effect of the natural flavone acacetin and its congeners in coronary-perfused human and canine right and left ventricular wedge and Langendorff-perfused whole-heart models of BrS and ERS generated by pharmacologically mimicking the genetic defects underlying these syndromes. Validation of the pharmacologic models as surrogates for the genetic syndromes will be performed by examining the characteristics of induced pluripotent stem cell-derived cardiomyocytes derived from peripheral blood mononuclear cells of patients with BrS and ERS, and their response to acacetin. A second principal aim of the proposed study is to evaluate the potential synergy of the combination of acacetin and quinidine. We will test the hypothesis that relatively low concentrations of the two agents are effective in suppressing the ECG and arrhythmic manifestation of BrS and ERS. The QT-prolonging effects of quinidine are expected to counter the QT abbreviating effect of acacetin, and vice versa, leading to safer use of both agents. The use of lower concentrations of quinidine is also expected to lower the dose of quinidine to levels at which the gastrointestinal-side-effects are avoided, making the drug better tolerated by patients. A third principal aim is to elucidate the selectivity for inhibition of Ito by congeners of acacetin with 80% to 96% similarity of molecular structure in a search for more Ito-selective blockers. Successful completion of these specific aims will importantly advance our ability to pharmacologically suppress arrhythmogenesis associated with the J-wave syndromes and provide further understanding of the cellular and ionic mechanisms involved in the pathogenesis of these syndromes, and provide a unique platform for the development of novel therapies that could potentially find their way to the bedside. 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 potentially at risk for sudden cardiac death, and for whom an ICD is not indicated by current guidelines. An early repolarization pattern is observed in 2% to 5% of the US population and until approximately a decade ago was thought to be totally benign. While it is clear that the vast majority of individuals exhibiting an early repolarization pattern are not at risk for sudden cardiac death (SCD), our challenge moving forward is to identify those individuals who truly are at risk and to design safe and effective treatments. The proposed study is a critical step in the ultimate achievement of these goals.


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: 2021 ( Subtotal = $0 )
2021	2018	LANKENAU INSTITUTE FOR MEDICAL RESEARCH	100 E LANCASTER AVE	WYNNEWOOD	PA	19096	MONTGOMERY	USA	Cardiovascular Diseases Research	000	1	3/10/2021	NEW	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $0 )
2019	2018	LANKENAU INSTITUTE FOR MEDICAL RESEARCH	100 E LANCASTER AVE	WYNNEWOOD	PA	19096	MONTGOMERY	USA	Cardiovascular Diseases Research	000	1	12/18/2018	NEW	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $412,500 )
2018	2018	LANKENAU INSTITUTE FOR MEDICAL RESEARCH	100 E LANCASTER AVE	WYNNEWOOD	PA	19096	MONTGOMERY	USA	Cardiovascular Diseases Research	000	1	9/11/2018	NEW	$412,500
														Subtotal = $412,500

Grand Total All Awards = $412,500

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Novel Approaches to Pharmacologic Management of Life-Threatening Arrhythmias Associated with the J Wave Syndromes

Award Number: R56HL138103

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/15/2018

PERIOD OF PERFORMANCE END DATE: 08/31/2020

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