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Biological substrate modification to suppress ventricular arrhythmias in a porcine model of chronic ischemic cardiomyopathy

Award Number: R01HL164896
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2022
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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Biological substrate modification to suppress ventricular arrhythmias in a porcine model of chronic ischemic cardiomyopathy - PROJECT SUMMARY/ABSTRACT Cardiomyopathy patients are prone to ventricular arrhythmias (VA) and sudden death. Current therapies to prevent VA include radiofrequency ablation to destroy slowly conducting pathways of viable myocardium which support re-entry. Here we propose to test the reverse concept, namely that boosting local tissue viability in zones of slow conduction might eliminate slow conduction and suppress VA. We seek to do so by local injection, into mapped areas of slow conduction, of exosomes secreted by cardiosphere-derived cells (CDCs), a stromal/progenitor cell type from the human heart. Exosomes are extracellular vesicles laden with bioactive cargo. Those secreted by CDCs (CDCEXO) reduce scar and improve heart function after intramyocardial delivery. In a VA-prone porcine model of ischemic cardiomyopathy, we present preliminary data in which we injected CDCEXO or vehicle into zones of delayed conduction defined by electroanatomic mapping. Up to one month post- injection, CDCEXO, but not vehicle, decreased myocardial scar, suppressed slowly conducting electrical pathways, and inhibited VA induction by programmed stimulation. In silico reconstruction of electrical activity based on magnetic resonance images accurately reproduced the suppression of VA inducibility by CDCEXO. Here we will explore alternative intracoronary delivery methods which would be more readily translatable clinically than the intramyocardial injection approach, which requires non-approved catheters. We will also explore mechanism of the anti-VA effects histologically and by RNA sequencing, as well as in a co-culture assay of cardiomyocytes and fibroblasts. We will also compare directly the efficacy of exosomes versus conventional RF ablation. In conclusion, we seek to establish biological substrate modification by exosome injection as a nondestructive alternative to conventional ablation for the prevention of recurrent ventricular tachyarrhythmias.


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: 2024 ( Subtotal = $724,148 )
2024	2024	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Cardiovascular Diseases Research	000	3	8/13/2024	NON-COMPETING CONTINUATION	$724,148
														Subtotal = $724,148

Issue Date FY: 2023 ( Subtotal = $730,577 )
2023	2023	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Cardiovascular Diseases Research	000	2	8/11/2023	NON-COMPETING CONTINUATION	$730,577
														Subtotal = $730,577

Issue Date FY: 2022 ( Subtotal = $730,577 )
2022	2022	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Cardiovascular Diseases Research	000	1	8/31/2022	NEW	$730,577
														Subtotal = $730,577

Grand Total All Awards = $2,185,302

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Biological substrate modification to suppress ventricular arrhythmias in a porcine model of chronic ischemic cardiomyopathy

Award Number: R01HL164896

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2022

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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