Activation of Hypothalamic Oxytocin Neurons Mitigates Cardiac Dysfunction in an Animal Model of Heart Failure

A distinctive hallmark of heart failure (HF) is autonomic imbalance; increased sympathetic activity and decreased parasympathetic tone. While the clinical significance of sympathetic over-activation is well established and forms the rationale for beta-blockers and other sympathetic targets central to standard HF therapies, parasympathetic regulation and its modulation has received much less attention. Recent work from our group has shown selective stimulation of hypothalamic paraventricular nucleus (PVN) oxytocin (OXT) neurons activate parasympathetic cardiac vagal neurons in the brainstem. PVN OXT neuron activation reduced heart rate and blood pressure in sham animals and prevented the hypertension and tachycardia that occurs in an animal model of sleep apnea (OSA). Our recent study in patients with OSA show intranasal oxytocin increases parasympathetic cardiac activity and decreases obstructive durations.

In this study we tested if PVN OXT neuron activity improves cardiovascular function in an animal model of HF. Rats underwent trans-ascending aortic constriction (TAC) to induce left ventricular (LV) hypertrophy that progresses to HF. In a subset of HF rats, PVN OXT neurons were chronically activated by selective expression and activation of excitatory DREADDS receptors. The group treated with OXT neuron activation had significantly improved measures of cardiac function and diminished markers of ischemia and fibrosis. Myocyte cross-sectional area and collagen density in hearts from treatment animals (oxytocin activated) were less than that of diseased animals. Left ventricular developed pressure (LVDP), coronary flow rate, contractility, and relaxation were all lower for disease hearts compared to hearts from treatment animals. In addition, cardiac contractility and relaxation parameters were significantly improved in treatment animals. In telemetry-instrumented animals activation of PVN OXT neurons mitigates exercise intolerance, cardiac dysfunction and pro-arrhythmic EKG abnormalities. These results indicate PVN OXT neuron activation can elevate cardio-protective parasympathetic tone, which in turn improves cardiac function in an animal model of HF.