Poster BB20 - Outcomes of selective hypothalamic neuron activation in preclinical heart failure with preserved ejection fraction

Introduction: Cardiovascular diseases are the leading cause of death globally. Among these, heart failure with preserved ejection fraction (HFpEF), commonly referred to as diastolic heart failure, exhibits a higher prevalence among older women with comorbidities such as hypertension, diabetes, dyslipidemia, and obesity. This study investigates the cardio-respiratory outcomes of selectively activating hypothalamic neurons to bolster parasympathetic tone, presenting a novel treatment paradigm for HFpEF.

Materials and

Methods: In this study, p5 female Sprague Dawley rats underwent stereotactic injections of oxytocin-Cre promoter and hM3Dq DREADDs at the paraventricular nucleus (PVN) of the hypothalamus. Following a 12-week period, the HFpEF phenotype was induced through ovariectomy, a high fat-high sugar diet for 36 weeks, and exposure to chronic intermittent hypoxia (CIH). Two treatment approaches were assessed for their efficacy in improving cardiac function: central activation of oxytocin neurons (PVN OXT) via daily intraperitoneal (IP) clozapine-N-oxide (CNO) injections (n=8), and peripheral activation through IP oxytocin injections (IP OXT) (n=4). Statistical analysis involved comparing differences between groups using one-way ANOVA with multiple comparisons.

Results, Conclusions, and Discussions: Echocardiographic results revealed that the additional cardiorespiratory injury induced by CIH exposure manifested characteristic changes consistent with HFpEF, including a reduced E/A ratio (p = 0.0006) and increased E/E' (p = 0.0101) compared to animals without exposure. Notably, IP OXT administration mitigated the decrease in E/A ratio associated with CIH exposure (p = 0.0006), while both PVN OXT and IP OXT delivery attenuated E/E’ increases (p = 0.0001). Furthermore, histological analysis indicated that both PVN OXT and IP OXT administration reduced fibrosis development, suggesting a potential mechanism for the observed benefits.
In our preclinical model, activation of oxytocin neurons improves diastolic function and blunts the progression of HFpEF. These findings underscore the potential therapeutic value of oxytocin neuron activation in HFpEF treatment and support further investigation into the underlying mechanisms of action.

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