High Fat Diet‐Induced Plasticity in Parasympathetic Heart Rate Control: A Novel Mechanism for Cardiovascular Disease?

Abstract

The pathological link between consumption of fat and the development of cardiovascular disease (CVD) has long been established. Still, the obesity‐independent mechanisms through which a high fat diet (HFD) contributes to the pathogenesis of CVDs like cardiac arrhythmias remain elusive. A wealth of preclinical, clinical, and epidemiological data has conclusively linked autonomic nervous system dysfunction—characterized by a potentiation of sympathetic activity, and a decrease in parasympathetic vagal tone—to a broad spectrum of cardiovascular diseases, including cardiac arrhythmias. Recent studies report that short‐term dietary consumption of a HFD induces sympathoexcitation and decreased cardiac parasympathetic tone in both animals and humans, suggesting autonomic dysfunctions occur well before the onset of overt obesity where aberrant metabolic dysregulations are evident. Presently, the majority of preclinical and clinical cardiovascular research targets sympathetic nervous system hyperactivity. Despite these advances, a significant clinical unmet need remains for alternative therapeutic strategies, especially for patients resistant to current pharmacotherapy interventions. In the present study, we investigated the mechanism by which HFD—independent of obesity—induces a decrease in cardiac parasympathetic tone, which is not presently understood. We hypothesized that HFD‐mediated increases in inhibitory current to cardiac vagal motoneurons lead to a decrease in cardiac vagal drive, thereby increasing CVD susceptibility.Our approach initially employed in vivo heart rate (HR) telemetry to monitor HFD‐induced alterations in HR. At the conclusion of the two weeks of HFD exposure, HFD‐fed mice exhibited a significant increase in food intake at day one of HFD exposure. This was not accompanied by significant changes in food intake, blood glucose levels, or body weight throughout the remaining duration of both diets. HR telemetry findings indicated that mice challenged with HFD for a two‐week period did not show significant changes in HR or HR variability parameters like RMSSD, HF power, or the LF/HF ratio compared to controls. Interestingly, pharmacological blockade of the parasympathetic and sympathetic nervous systems during HR telemetry recording suggested there is a preferential dysfunction in parasympathetic drive in animals fed HFD compared to control chow‐fed mice. When challenged with a bolus injection of glucose, HFD‐fed mice exhibited significantly higher blood glucose levels 30, 60, and 120 minutes after the injection. These changes were accompanied by a significantly higher HR at 15 minutes after injection. To determine if cardiac motoneuron output might play a role, we employed retrograde tracing to identify cardiac‐projecting nucleus ambiguus neurons and in vitro whole‐cell patch‐clamp electrophysiology to assess their signaling properties under control and HFD conditions. Our findings suggest that increasing parasympathetic drive prior and during HFD exposure may be a promising therapeutic target for preventing the aberrant effects of a HFD on HR.Support or Funding InformationAmerican Heart Association 16SDG26590000 to CRB and NIH Initiative for Maximizing Student Development grant R25GM095480‐08 to LE.