Spencer Fox Eccles School of Medicine
47 Cardiac Adrenergic Stimulation in a Zebrafish Model of Human Atrial Fibrillation
Leah Moellmer; Martin Tristani-Firouzi; Natalia S. Torres; Christopher Kauffman; and Ainsley Hokanson
Faculty Mentor: Martin Tristani-Firouzi (Pediatrics, University of Utah)
Abstract
Atrial fibrillation is a cardiac arrhythmia characterized by an irregular heartbeat in the atrial chambers of the heart. Our previous work has identified the Nuclear Factor of Activated Tcells (NFATC1) as a novel atrial fibrillation susceptibility gene for familial atrial fibrillation (phenotype appearing at <40 years old). NFATC1 is known to be involved in cardiac development, but the link to arrhythmias has not been previously established. Using CRISPR/Cas9 we generated a nfatc1 knock-out (KO) zebrafish transgenic line that showed an increased presence of arrhythmogenic events and a sudden death phenotype in juvenile f ish. Our current objective is to determine whether the absence of nfatc1 influences heart function and response to stress in zebrafish embryos (48- to 120-hours post-fertilization (hpf)). Larvae heart rate was then measured in the presence of 100 μM of isoproterenol (a β-adrenergic agonist) to test their response to adrenergic stimulation. We observed that the heart rates followed the expected increase with age but were not statistically different between genotypes for the same developmental stage. Furthermore, the addition of isoproterenol did not elicit arrhythmias in either genotype. Taken as a whole, these results suggest that nfatc1 does not affect heart rate or response to adrenergic stimulation in early developmental stages. These findings suggest that an impairment in the nfatc1 gene function may be more relevant in the juvenile heart, which is in line with an early onset atrial fibrillation phenotype observed in humans.
Introduction
Atrial fibrillation (AF) is the most common group of cardiac arrhythmias, causing over 28,000 deaths in 2021 (CDC, 2024). This mortality rate is a result of AF causing a significant increase in the risk of stroke, heart failure, and general mortality (Workman, 2010). AF occurrence can be caused by activity in the adrenergic (sympathetic) or cholinergic (parasympathetic) divisions of the autonomic nervous systems (Workman, 2010). The adrenergic division is responsible for the body and heart’s response to stress. Activation of adrenergic systems results in an increase in heart rate, as well as an increase in the force with which the ventricles contract.(Scanlon & Sanders, 2006). Stimulation of the adrenergic division releases adrenergic hormones and catecholamines which bind to the α and β adrenoreceptors that are present in the heart (Workman, 2010).
Isoproterenol is a synthetic agonist that only binds to β receptors (Kuhar et al., 1999). These are the adrenergic receptors most common in the heart. Additionally, a study has found that infusion of isoproterenol produces AF in 5% of patients wit