Basic/Translational Science -> Cell Physiology, Pharmacology, and Signaling D-PO02 - Poster Session II (ID 47) Poster

D-PO02-017 - Functional Consequences Of The E11k Mutation In The Atrial Myosine Light Chain 4 (myl-4) Gene Associated With Atrial Fibrillation (ID 162)

Disclosure
 E. Marcoux: Nothing relevant to disclose.

Abstract

Background: E11K mutation of the MYL-4 gene, involved in actin-myosin interaction in the atria, was recently associated with an atrial cardiomyopathy that evolves in an early onset of atrial fibrillation (AF) in an Icelandic cohort. More recently, E11K knock-in (KI) was shown to induce structural and electrical remodeling of the atria in a rat model.
Objective: This study addresses the electrophysiological remodeling and arrhythmias assessments in E11K-KI rats.
Methods: Cardiac structure and function integrity and AF susceptibility were respectively assessed by echocardiography, telemetry and electrical programmed stimulation (EPS) on 1-month old (m.o) KI rats. Right atria (RA) and left atria (LA) functions were studied by transthoracic echocardiography (TTE). Relative gene expression of relevant markers was assessed by qPCR. Fibrosis study was performed by Masson-Trichrome coloration.
Results: AF episodes were induced with EPS in 5/9 E11K-KI 1 m.o rats vs 0/6* in WT (*P<0.05). Continuous telemetry recordings prolonged PR interval in E11K-KI rats (PR = 54 ± 3 ms* KI, PR = 43 ± 2ms*** WT ). Collagen mRNA expression showed an increase of Col1a1 (119% of increase) and Col3a1 genes (83% of increase) in the LA. Among calcium homeostasis-related genes, one was significantly decreased [Na+/Ca2+ exchanger ], and some follow this trend phospholamban , ATP-dependent Ca2+ pump , Ryanodine Receptor2 in young KI rats. Masson-trichrome revealed fibrosis of both RA WT= 4.3 ± 0.5 vs KI= 11.5% ± 1.7%*** (P<0.001) and LA WT= 2.7 ± 0.4% vs KI= 14.0 ± 1.9 %****(P<0.0001). TTE showed dilation of RA KI= 3.65* ± 0.07 vs WT= 3.23 ± 0.06 (P<0.05) and LA dilation WT= 3.5 ± 0.1 vs KI= 3.9* ± 0.1 (P<0.05). LA E/A ratio was increased in KI rats KI=1.59* ± 0.07 vs WT=1.41 ± 0.05 (P<0.05) and RA E/A ratio was increased in KI rats KI=1.26* ± 0.04 vs WT=1.07 ± 0.06 (P<0.05).
Conclusion: E11K mutation induces electrical and structural remodelling of both atria through collagen expression and deposition. 1 m.o old KI rats showed an alteration in genes expression that are known to regulate calcium homeostasis. Future experiments on 3 and 6 m.o rats will be conducted to characterize the atrial remodelling progression due to the mutation, in order to better understand the underlying mechanisms linking the cardiomyopathy to AF.
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