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"Outside-in” Model of Cardiac Pacemaking: Extracellular Mediated Automaticity

Award Number: R01HL175577
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/15/2025
PERIOD OF PERFORMANCE END DATE: 04/30/2029

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"Outside-in” Model of Cardiac Pacemaking: Extracellular Mediated Automaticity - Abstract The heart’s native pacemaker complex, the sinoatrial node (SAN), is a multicellular bioelectric signaling center responsible for rhythmically initiating the impulses that drive cardiac contraction. SAN dysfunction is extremely prevalent in humans and represents one of the leading causes for the surgical implantation of artificial pacing devices. SAN dysfunction is a progressive and noncurable. To date the molecular pathophysiology of SAN dysfunction remains poorly understood. Indeed, significant gaps remain in even our basic understanding of the biophysical processes that control electrical impulse generation in the heart. This is compounded by the fact that major discrepancies still exist between our theoretical descriptions of SAN electrical activation and experimental data. Therefore, we have used a combination of in vivo experimentation and computational modeling to reevaluate fundamental principles of cardiac pacemaking. More specifically, we have modeled how extracellular ion dynamics can influence the behavior of excitable cells arranged within fixed tissue geometries. This has revealed that robust entrained automaticity can emerge within cellular networks through repetitive elevation/depletion of extracellular potassium [K+]o. The stability of this automaticity is highest when [K+]o is elevated within diffusion limited extracellular nanodomains that are accessed by multiple cells. In addition, our model predicts that entrained automaticity can be achieved even when not all cells within a population are natively autorhythmic or connected via gap junctions. We have termed this form of “outside-in” regulation of pacemaking Extracellular Mediated Automaticity (EMA). In support of our computational simulations we have localized [K+]o within intact embryonic SAN tissue and identified that: i) [K+]o is indeed elevated in nanodomains between adjacent cardiac pacemaker cells (CPCs) in the SAN, ii) [K+]o oscillates within these nanodomains in a manner predicted by EMA, and iii) depletion of [K+]o from these nanodomains results in rapid loss of SAN automaticity and entrainment. Collectively these data have led to our overall working hypothesis that extracellular ion cycling serves as a baseline mechanism for imparting rhythmic, multicellular, impulse generation in the SAN. This hypothesis will be tested across two specific aims in which we will define [K+]o as the critical ionic species that underlies this form of entrained CPC automaticity (Aim1) and identify the mechanisms that control nonuniform extracellular ion distribution within the SAN (Aim2). Thus, successfully completion of the proposed studies will uncover an entirely novel set of paradigms for coupled electrical oscillation in the SAN and identify new extracellular regulators of SAN function. These data will fundamentally alter current theories of cardiac pacemaking, identify new factors to target as causative for SAN dysfunction, and directly inform future design criteria for clinical restoration of homologous biological pacemaking in patients.


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 = $680,708 )
2026	2026	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cardiovascular Diseases Research	001	2	5/20/2026	NON-COMPETING CONTINUATION	$680,708
2026	2025	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cardiovascular Diseases Research	000	1	4/25/2026	NEW	$0
														Subtotal = $680,708

Issue Date FY: 2025 ( Subtotal = $668,783 )
2025	2025	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cardiovascular Diseases Research	000	1	7/15/2025	NEW	$668,783
														Subtotal = $668,783

Grand Total All Awards = $1,349,491

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"Outside-in” Model of Cardiac Pacemaking: Extracellular Mediated Automaticity

Award Number: R01HL175577

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/15/2025

PERIOD OF PERFORMANCE END DATE: 04/30/2029

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