Chemogenetic Activation of Paraventricular Oxytocin Neurons Reduces Cardiac Dysfunction During Heart Failure

There is a distinctive cardiac autonomic imbalance in HF consisting of increased sympathetic activity and decreased parasympathetic tone. Recent work has indicated that activation of paraventricular nucleus (PVN) oxytocin neurons increases co-release of oxytocin with glutamate to elevate cardiac vagal tone yet little is known regarding the long-term (16 week) benefit. We hypothesize that activation of oxytocin neurons in the PVN will blunt the progression of HF by reducing inflammation and fibrosis at 16 weeks post-HF initiation than in untreated counterparts. Rats underwent trans-ascending aortic constriction (TAC) to induce HF. In a subset of HF rats (TAC+OXT), oxytocin neurons were activated by excitatory designer receptors exclusively activated by designer drugs (DREADDs). Rats were implanted with ECG telemetry devices and underwent a treadmill protocol to measure peak effort capacity and heart rate recovery (HRR). Cardiac structural measurements were obtained using echocardiography. After 16 weeks, hearts were rapidly excised, Langendorff perfused to measure mechanical function, and prepared for histology and western blot analysis. Indices of cardiac function (stroke volume, ejection fraction, cardiac output, and fractional shortening) indicated preserved function in TAC+OXT compared to TAC. HRR after peak effort capacity values were lowest in TAC and were significantly greater in TAC+OXT (p≤0.05), indicating preservation of cardiac parasympathetic tone. LV developed pressure was significantly impaired in TAC compared to sham as well as significantly improved in TAC+OXT compared to TAC (p≤0.05). Contractility and relaxation were significantly impaired in TAC compared to sham (p≤0.05), while TAC+OXT animals had values not different from sham. TAC animals had collagen III levels 5X higher than TAC+OXT. Histological analysis indicated increased fibrosis in disease groups compared to sham. TAC+OXT had IL-1β levels significantly lower than TAC (p≤0.05). PVN oxytocin neuron activation slows the decline of cardiac function in 16 week post- TAC rats, likely by reinstating cardioprotective parasympathetic activity. This novel method has translational potential since intranasal oxytocin administration has been used in the clinic.