Carotid body-mediated chemoreflex drive predicts the development of HFpEF in mice

Abstract

Heart failure with preserved ejection fraction (HFpEF) is a prevalent pathophysiological condition affecting millions of people worldwide. Several factors have been pointed out to play a role in the development of HFpEF; however, there are no molecular/physiological variables that can predict the incidence of HFpEF. Interestingly, carotid body (CB) chemoreceptors have been implicated in worse outcomes in reduced ejection fraction HF. Then, we hypothesized that CB chemoreflex sensitivity may offer prognostic value in HFpEF. Accordingly, we aimed to study whether high chemoreflex drive predicts the development of HFpEF in mice. A longitudinal study was performed in adult C57BLJ6 mice (P90) that underwent 16 weeks treatment with a high fat diet (60% high fat diet, HFD) and a nitric oxide synthase blocker (L-NAME 0.6 g/L) to induce HFpEF. Mice were recorded for cardiac/hemodynamic and ventilatory function before the onset of HFD and L-NAME treatment by using 2D-echocardiography, tissue doppler imaging, blood pressure and whole-body plethysmography, respectively. At 16 weeks after HFD+L-NAME all mice were recorded again. CB-chemoreflex drive was assessed by the hypoxic ventilatory response (HVR, FiO2»10%). We found that »50% of total mice (n=24) develop HFpEF after 16 weeks of HFD+L-NAME as evidenced by a significant (p<0.05) increase in the E/A ratio (1.60±0.09 vs. 1.30±0.01 mmHg, HFpEF vs. nonHFpEF), blood pressure (MAP: 98.7±1.9 vs. 88.4±1.4 mmHg, HFpEF vs. nonHFpEF) and body weight (31±1 vs. 29±0 g, HFpEF vs. nonHFpEF). Remarkably, a higher HVR before the onset of HFD+L-NAME was closely associated with the prevalence of HFpEF. Indeed, (4/5) mice that displayed a high HVR chemoreflex (³0.15 ΔVE/FiO2%) develop HFpEF after 16 weeks of HFD+L-NAME treatment. Our results showed for the first time that CB-mediated chemoreflex sensitivity predicts the development of HFpEF and support the notion that peripheral chemoreflex drive may be useful to evaluate the risk of developing HFpEF. Supported by Fondecyt 1220950. 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.