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Partial and Controlled Depletion of SR Calcium by RyR Agonists Prevents Calcium-dependent Arrhythmias

Award Number: R01HL167195
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2023
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Partial and Controlled Depletion of SR Calcium by RyR Agonists Prevents Calcium-dependent Arrhythmias - ABSTRACT Sympathetic stimulation of ventricular myocytes activates PKA, which phosphorylates L-type Ca2+ channels and phospholamban, among other substrates, to increase Ca2+ entry and SR Ca2+ uptake. This β- adrenergic-induced increase of intracellular Ca2+ (Ca2+ overload) is a natural and efficient mechanism to increase cardiac performance, inasmuch as the magnitude and force of cardiac contractions greatly depend on the amount of Ca2+ supplied to the myofilaments. However, Ca2+ overload also increases arrhythmia vulnerability because it brings ryanodine receptors (RyR2) closer to threshold for spontaneous Ca2+ release (SCR). SCR during diastole activates the Na+/Ca2+ exchanger of the sarcolemma and generates a depolarizing inward current (delayed after-depolarization or DAD) that may trigger extemporaneous actions potentials. Ca2+ overload and its subsequent SCRs are indeed the primary events that evolve in malignant cardiac arrhythmias, as observed in Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) and quite possibly in some forms of atrial fibrillation, long QT, and heart failure. To prevent these Ca2+-dependent arrhythmias, an emergent group of RyR2 blockers aim to stop SCR, despite the fact that the key process that spawns SCR, namely, Ca2+ overload, may not be affected or in some cases may be even exacerbated by the RyR2 blockers. We have found that imperacalcin, a high-affinity, membrane-permeable selective agonist of RyRs, paradoxically decreases arrhythmia burden and prevents Ca2+-dependent arrhythmias in animal models of CPVT. We hypothesize that this unexpected and remarkable anti-arrhythmic effect of imperacalcin is due to a partial and controlled depletion of SR Ca2+ load, which decreases the propensity of SCR events and thus dissipates the main arrhythmogenic substrate in CPVT. Our research program will systematically and rigorously test this hypothesis at the molecular, cellular, whole heart and intact animal levels using established (mouse) and novel (rabbit) models of CPVT. The first specific aim will determine the defining structural and functional characteristics that confer to imperacalcin and other members of the calcin family their capacity to permeate membranes and their anti-arrhythmic properties. In the second aim, we will use native and modified calcins on intact cardiomyocytes, Langendorff-perfused working hearts and intact animals for a rationalized design of a novel group of RyR2 ligands capable of preventing Ca2+-triggered arrhythmias. These studies use animal models of CPVT to develop a novel paradigm for the treatment of Ca2+ overload-generated cardiac arrhythmias; results may be applied to other cardiomyopathies where controlled unloading of SR Ca2+ may be desirable.


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: 2026 ( Subtotal = $585,974 )
2026	2026	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Cardiovascular Diseases Research	000	4	2/23/2026	NON-COMPETING CONTINUATION	$585,974
														Subtotal = $585,974

Issue Date FY: 2025 ( Subtotal = $616,814 )
2025	2025	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Cardiovascular Diseases Research	000	3	1/1/2025	NON-COMPETING CONTINUATION	$555,132
2025	2025	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Cardiovascular Diseases Research	001	3	7/24/2025	NON-COMPETING CONTINUATION	$61,682
														Subtotal = $616,814

Issue Date FY: 2024 ( Subtotal = $604,478 )
2024	2024	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Cardiovascular Diseases Research	000	2	12/18/2023	NON-COMPETING CONTINUATION	$555,132
2024	2024	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Cardiovascular Diseases Research	001	2	6/8/2024	NON-COMPETING CONTINUATION	$49,346
														Subtotal = $604,478

Issue Date FY: 2023 ( Subtotal = $616,814 )
2023	2023	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Cardiovascular Diseases Research	000	1	12/15/2022	NEW	$616,814
														Subtotal = $616,814

Grand Total All Awards = $2,424,080

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Partial and Controlled Depletion of SR Calcium by RyR Agonists Prevents Calcium-dependent Arrhythmias

Award Number: R01HL167195

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2023

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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