Chemogenetic activation of PVN-OXT neurons following acute myocardial infarction improved 7-day survival to 95% compared to 85% in untreated rats, while preserving mitochondrial function.
Does chemogenetic activation of PVN-OXT neurons improve survival, autonomic balance, and cardiac function in a rat model of acute myocardial infarction?
Chemogenetic activation of hypothalamic oxytocin neurons early after myocardial infarction preserves parasympathetic tone, reduces arrhythmias, and improves survival in a rat model.
Absolute Event Rate: 95% vs 85%
Altered autonomic balance is a hallmark of numerous cardiovascular diseases, including myocardial infarction (MI). Although device-based vagal stimulation is cardioprotective during chronic disease, a non-invasive approach to selectively stimulate the cardiac parasympathetic system immediately after an infarction does not exist and is desperately needed. Cardiac vagal neurons (CVNs) in the brainstem receive powerful excitation from a population of neurons in the paraventricular nucleus (PVN) of the hypothalamus that co-release oxytocin (OXT) and glutamate to excite CVNs. We tested if chemogenetic activation of PVN-OXT neurons following MI would be cardioprotective. The PVN of neonatal rats was transfected with vectors to selectively express DREADDs within OXT neurons. At 6 weeks of age, an MI was induced and DREADDs were activated with clozapine-N-oxide. Seven days following MI, patch-clamp electrophysiology confirmed the augmented excitatory neurotransmission from PVN-OXT neurons to downstream nuclei critical for parasympathetic activity with treatment (43.7 ± 10 vs 86.9 ± 9 pA; MI vs. treatment), resulting in stark improvements in survival (85% vs. 95%; MI vs. treatment), inflammation, fibrosis assessed by trichrome blue staining, mitochondrial function assessed by Seahorse assays, and reduced incidence of arrhythmias (50% vs. 10% cumulative incidence of ventricular fibrillation; MI vs. treatment). Myocardial transcriptomic analysis provided molecular insight into potential cardioprotective mechanisms, which revealed the preservation of beneficial signaling pathways, including muscarinic receptor activation, in treated animals. These comprehensive results demonstrate that the PVN-OXT network could be a promising therapeutic target to quickly activate beneficial parasympathetic-mediated cellular pathways within the heart during the early stages of infarction.
Schunke et al. (Fri,) conducted a other in Acute myocardial infarction. Chemogenetic activation of PVN-OXT neurons via clozapine-N-oxide (CNO) vs. Saline injections was evaluated on Survival at 7 days post-MI. Chemogenetic activation of PVN-OXT neurons following acute myocardial infarction improved 7-day survival to 95% compared to 85% in untreated rats, while preserving mitochondrial function.