Abstract Body: Introduction
Obscurin is a giant cytoskeletal protein that supports muscle development, tethers intracellular compartments to the sarcolemma, and regulates contraction. In the ObscnΔIg58/59 mouse model, expressing obscurin lacking Immunoglobulin (Ig) domains 58 and 59, males exhibit atrial fibrillation accompanied by atrial and ventricular dilation. Following extensive characterization of male ObscnΔIg58/59 ventricles and atria, we uncovered that atria are principally and particularly affected by Ig58/59 elimination and that the ObscnΔIg58/59 model mirrors essential aspects of atrial cardiomyopathy. Critically, ObscnΔIg58/59 females are phenotypically normal.
Hypotheses
We sequentially postulated that a) ovarian estrogens and b) dietary phytoestrogens insulate ΔIg58/59 females against cardiac remodeling and arrhythmias.
Methods
We a) surgically excised the ovaries (OVX) of young ObscnΔIg58/59 females, or performed sham bilateral surgery and b) switched them to a soy-free (phytoestrogen-free) chow. We then analyzed heart form and function in Sham/OVX WT and ΔIg58/59 females via echocardiogram and electrocardiogram.
Results
Depletion of endogenous and exogenous estrogens induced age-specific remodeling of the left ventricle in ΔIg58/59 females yet failed to provoke progressive arrhythmias.
Conclusions and Ongoing Studies
We theorize that c) extragonadal estrogens and/or d) the relative absence of androgens sustain sinus rhythm in soy-free, OVX ObscnΔIg58/59 females. Consequently, we are currently examining how long-term delivery of the c) aromatase inhibitor letrozole and d) the nonaromatizable androgen dihydrotesterone impact heart morphology and rhythmicity in soy-free, OVX ΔIg58/59 females. Collectively, our work challenges the notion that ovarian sex hormones singlehandedly support female cardioprotection and suggests that additional hormonal and perhaps chromosomal factors shield female hearts from dysfunction downstream of Ig58/59 deletion.