Accumulation of Pericardial Fat Is Associated with Alterations in Heart Rate Variability Patterns in Hypercholesterolemic Pigs

Abstract

Background - Heart rate variability (HRV) or pulse rate variability are indices of autonomic cardiac modulation. Increased pericardial fat is associated with worse cardiovascular outcomes. We hypothesized that progressive increases in pericardial fat volume and inflammation prospectively dampen HRV in hypercholesterolemic pigs. Methods - Wild-type (WT) or PCSK9 gain-of-function Ossabaw mini-pigs were studied in-vivo before and after 3- and 6-months of a normal-diet (WT-ND n=4, PCSK9-ND n=6) or high-fat diet (WT-HFD n=3, PCSK9-HFD n=6). The arterial pulse waveform was obtained from an arterial telemetry transmitter to analyze HRV indices, including standard deviation (SDNN), root-mean-square of successive differences (RMSSD), proportion >50 milliseconds (pNN50) of normal-to-normal RR-intervals, and the calculated ratio of low-to-high frequency distributions (LF/HF). Pericardial fat volumes were evaluated using multidetector computed-tomography, and its inflammation by gene expression of tumor necrosis-factor (TNF)-α. Plasma lipid panel and norepinephrine level were also measured. Results - At diet completion, hypercholesterolemic PCSK9-HFD had significantly (p<0.05 vs. baseline) depressed HRV (SDNN, RMSSD, pNN50, HF, LF), and both HFD groups had higher sympathovagal balance (SDNN/RMSSD, LF/HF) compared to ND. Pericardial fat volumes and LDL-C concentrations correlated inversely with HRV and directly with sympathovagal balance, while sympathovagal balance correlated directly with plasma norepinephrine. Pericardial fat TNF-α expression was upregulated in PCSK9-HFD, co-localized with nerve fibers, and correlated inversely with RMSSD and pNN50. Conclusions - Progressive pericardial fat expansion and inflammation are associated with a fall in HRV in Ossabaw mini-pigs, implying aggravated autonomic imbalance. Hence, pericardial fat accumulation is associated with alterations in HRV and the autonomic nervous system.