17 β-Estradiol ameliorates cardiac parasympathetic dysfunction following myocardial infarction in male mice

Abstract

Background: Vagal dysfunction after chronic myocardial infarction (MI) is associated with an increased risk of ventricular tachycardia (VT)/ventricular fibrillation (VF) and increased mortality in heart failure. The incidence and outcomes of VT/VF are influenced by sex, with women having a lower incidence of VT/VF associated with ischemic heart disease. However, the mechanisms behind these sex differences remain unclear and could be due to sex differences in autonomic remodeling post-MI that is mediated by estrogen. Hypotheses: We hypothesized that estrogen improves vagal function after MI by reducing oxidative stress in vagal sensory neurons and improving vagal afferent/efferent reflexes and function. Methods: Mice with expression of channelrhodopsin (ChR2) in specific sensory afferent neurons were created by crossing vesicular glutamate transporter 2 (VGlut2)-IRES-Cre mice with ChR2-EYFP mice, and their offspring (Vglut2-ChR2-EYFP) used for optogenetic stimulation studies. Sham surgery (n=6) or MI (n=6) was performed in two separate groups of male mice. A third group of male mice (n=8) underwent 17β-Estradiol (E2) pellet (0.5 milligrams/pellet) implantation followed by MI (E2+MI) after 2.5 weeks. Terminal studies were performed 2-3 weeks post-MI/sham procedures by placing a blue light (473 nm) laser probe over the left cervical vagus in vivo to stimulate vagal sensory neurons (20 Hz, 10 & 20 msec stimulations for 5 sec). Heart rate (HR) and blood pressure (BP) responses were measured in response to optogenetic stimulation. Plasma E2 and nodose ganglion 4-hydroxynaneol (4HNE) levels, a marker of lipid peroxidation, were evaluated. Results: In response to optogenetic vagal stimulation, MI had reduced reflex heart rate responses vs. sham animals, while E2+MI mice demonstrated significantly better responses vs. MI and similar responses to sham animals (20 Hz, 10 msec: sham -59 ± 3%, MI -24 ± 3%, E2+MI -58 ± 4%, MI vs. E2+MI, P < 0.001; 20 Hz, 20 msec: sham -59 ± 4%, MI -31 ± 3%, E2+MI -60 ± 3%, MI vs. E2+MI, P < 0.001). In addition, while BP responses post-MI were reduced vs. sham, E2+MI male mice also demonstrated greater BP responses to optogenetic stimulation (20 Hz, 10 msec: sham -28 ± 4%, MI -12 ± 1%, E2+MI -27± 1%, MI vs. E2+MI, P < 0.001; 20 Hz, 20 msec: sham -32 ± 4%, MI -13 ± 1%, E2+MI -27 ± 5%, MI vs. E2+MI, P < 0.001). 4HNE levels were increased in MI vs. sham animals, while E2+MI mice demonstrated significant reductions in 4HNE levels (Sham 0.17 ± 0.09 μg/protein, MI 0.77 ± 0.11 μg/protein, E2±MI 0.26 ± 0.06 μg/protein, MI vs. E2+MI, P < 0.001). Finally, plasma measurements confirmed higher levels of estrogen in E2-implanted mice (MI 48 ± 10 pg/mL, E2+MI 850 ± 170 pg/mL, MI vs. E2+MI, P < 0.001). Conclusions: MI causes pathological vagal remodeling that is reflected in decreased sensory vagal neurotransmission and increased oxidative stress in the vagal ganglia. Parasympathetic dysfunction and oxidative stress are mitigated by estrogen, suggesting that estrogen may be an important factor in mitigating the resulting pathological autonomic remodeling post-MI that predisposes to VT/VF. NIHR01HL148190. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.