# Optimizing AF ablation by a novel optogenetics and computational approach

> **NIH NIH R21** · YALE UNIVERSITY · 2023 · $209,375

## Abstract

PROJECT SUMMARY
Atrial fibrillation (AF) is a major public health epidemic that impairs quality of life and is associated with increased
risk for stroke, heart failure, dementia, and death. Current therapeutic strategies for managing AF are highly
inadequate. Anti-arrhythmic drugs aimed at achieving rhythm control have limited efficacy and can elicit
ventricular pro-arrhythmia especially at advanced stages of the disease; whereas those directed at rate control
are only partially palliative as they focus on managing symptoms rather than reversing the arrhythmia itself. On
the other hand, radio-frequency ablation of the pulmonary veins, a corner stone of early AF management, is
highly effective for treating paroxysmal episodes of AF thatare typically initiated by calcium-mediated triggers
within this discrete region. Unfortunately, this anatomically-targeted approach is far less effective at more
advanced stages of this highly progressive disease. Indeed, patients with persistent AF exhibit significant
underlying atrial myopathy and widespread atrial structural and electrical remodeling. This, in turn, provides the
substrate for the perpetuation of AF through complex mechanisms involving the genesis of multiple wavelet
reentry with active sources (i.e. drivers) intermixed with passive bystanders.
effective
bystanders
ablation
overriding goal of this high-risk,
can
propose
(RQA)
guided
quantitative
in
destructive
cultures
AF
by a sarcolipin (SLN) promoter.
generation
generation,
A major obstacle to the delivery of
ablation l esion sets in this context is the difficulty of distinguishing bona-fide AF drivers from passive
at any given time. This complexity mandates the use of a trial & error approach for the delivery of
lesions which invariably leads to the unnecessary & irreversible destruction of atrial myocardium.
high-reward R21
fulfill the `learn-by-burn' paradigm without permanently destroying atrial myocardium. Towards this goal, we
 to: 1) identify sites of active AF drivers in pseudo real-time using recurrence quantification analysis
of local activation, 2) develop computational simulations of persistent AF and test the efficacy f RQA-
 vs unguided sets in terminating identical episodes of AF (not achievable experimentally); 3) develop
efficacy parameters that inform which steps of a lesion set are required and which are dispensable
altering AF dynamics prior to its termination; 4) use an inhibitory optogenetics based approach in which non-
 “erasable” AF ablation lesion sets can be delivered through customizable light-guided pulses in co-
of atrial-like hiPSC-CMs and fibroblasts, and 5) test ur approach in a genetic murine model of persistent
in which atrial-selective expression of the ptogenetics probe is achieved using
 Successful completion of these proof-of-concept studies wil l result in the
and validation of translatable methods that will bring the field a major step closer owards next
patient-specific ablation therapeutics for advance...

## Key facts

- **NIH application ID:** 10676183
- **Project number:** 5R21HL165147-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** FADI GABRIEL AKAR
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $209,375
- **Award type:** 5
- **Project period:** 2022-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10676183

## Citation

> US National Institutes of Health, RePORTER application 10676183, Optimizing AF ablation by a novel optogenetics and computational approach (5R21HL165147-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10676183. Licensed CC0.

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