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Pathophysiological Significance of Atrial Fibrillation Electrogram Patterns

Award Number: R01HL168117
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2023
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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Pathophysiological Significance of Atrial Fibrillation Electrogram Patterns - Atrial fibrillation (AF) is the most common heart rhythm disorder and is a major cause of stroke. Despite its rapidly rising incidence, current therapies are suboptimal. This is largely because current AF therapies, including ablation, are not targeted to the fundamental mechanisms underlying AF. AF is characterized by complex electrical activation patterns that are difficult to map using standard activation time mapping. Yet, there is growing evidence that AF is driven by stable sources in the atria, such as rotors or focal activity. Unfortunately, previous attempts to use AF electrograms to detect these sources have had mixed success. We have recently developed an electrogram morphology recurrence (EMR) analysis that appears to more accurately reflect molecular and electrophysiological substrate for AF than previously described AF electrogram measures of AF. Our recent studies suggest that regions of high recurrence morphology with the shortest cycle lengths (i.e. regions of low recurrence cycle length - CLR) may correspond to regions of increased parasympathetic innervation and/or increased oxidative injury. Furthermore, our clinical studies suggest that in patients with persistent AF, EMR mapping is both feasible and provides important physiologic information. Our overall hypothesis for this proposal is: ‘sites of high recurrence morphology with the shortest cycle length (i.e. CLR) represent regions of increased autonomic signaling and/or increased oxidative injury, which are critical to the maintenance of persistent AF.’ To test this hypothesis, we will use novel gene therapy approaches developed in our lab, as well as a CLR-guided ablation strategy in patients with persistent AF. In Specific Aim 1, we will assess in a canine rapid atrial pacing model of AF whether targeted inhibition of parasympathetic signaling – by expression of plasmids expressing Gαi/o inhibitory peptides (Gαi/o_ct) at the atrial sub-region with lowest CLR – will reverse electrical remodeling and AF. In Specific Aim 2, we will assess in the same canine model whether targeted inhibition one or more of the two major sources of oxidative injury in AF - by expression of NOX2 shRNA  mitochondrial catalase at the atrial sub-region with lowest CLR – will reverse electrical remodeling, prevent progression of fibrosis and decrease AF. In Specific Aim 3, patients with persistent AF who are undergoing catheter ablation will be randomized to a CLR guided ablation strategy or PVI alone; we will determine whether in these patients a CLR guided ablation strategy will increase ECG dominant frequency compared to PVI alone. Completion of all the aims will provide a clear path to using EMR mapping as a new diagnostic method to guide therapeutic intervention for AF. This proposal leverages the prior development and validation of EMR to test several novel targeted approaches for treating AF. As AF may have complex underlying pathophysiology, it is feasible that one or more of these approaches could be therapeutic and could ultimately be used in combination. This proposal provides a critical platform to advance the science of curative therapy for AF.


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: 2025 ( Subtotal = $679,066 )
2025	2025	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Cardiovascular Diseases Research	000	3	8/25/2025	NON-COMPETING CONTINUATION	$679,066
														Subtotal = $679,066

Issue Date FY: 2024 ( Subtotal = $678,959 )
2024	2024	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Cardiovascular Diseases Research	001	2	6/25/2024	NON-COMPETING CONTINUATION	$55,424
2024	2024	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Cardiovascular Diseases Research	000	2	4/26/2024	NON-COMPETING CONTINUATION	$623,535
														Subtotal = $678,959

Issue Date FY: 2023 ( Subtotal = $703,840 )
2023	2023	UNIVERSITY OF MIAMI	1400 NW 10TH AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Cardiovascular Diseases Research	000	1	6/30/2023	NEW	$703,840
														Subtotal = $703,840

Grand Total All Awards = $2,061,865

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Pathophysiological Significance of Atrial Fibrillation Electrogram Patterns

Award Number: R01HL168117

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2023

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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