Background: Heart rate variability (HRV) and 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: WT (wild type) or PCSK9 (proprotein convertase subtilisin-like/kexin type-9) gain-of-function Ossabaw mini-pigs were studied in vivo before and after 3 and 6 months of a normal diet (WT-normal diet, n=4; PCSK9-normal diet, n=6) or high-fat diet (HFD; WT-HFD, n=3; PCSK9-HFD, n=6). The arterial pulse waveform was obtained from an arterial telemetry transmitter to analyze HRV indices, including SD (SD of all pulse-to-pulse intervals over a single 5-minute period), root mean square of successive differences, proportion >50 ms of normal-to-normal R-R intervals, and the calculated ratio of low-to-high frequency distributions (low-frequency power/high-frequency power). Pericardial fat volumes were evaluated using multidetector computed tomography and its inflammation by gene expression of TNF (tumor necrosis factor)-α. Plasma lipid panel and norepinephrine level were also measured.
Results: At diet completion, hypercholesterolemic PCSK9-HFD had significantly (P<0.05 versus baseline) depressed HRV (SD of all pulse-to-pulse intervals over a single 5-minute period, root mean square of successive differences, proportion >50 ms, high-frequency power, low-frequency power), and both HFD groups had higher sympathovagal balance (SD of all pulse-to-pulse intervals over a single 5-minute period/root mean square of successive differences, low-frequency power/high-frequency power) compared with normal diet. Pericardial fat volumes and LDL (low-density lipoprotein) cholesterol 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, colocalized with nerve fibers, and correlated inversely with root mean square of successive differences and proportion >50 ms.
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. Visual Overview: A visual overview is available for this article.
Keywords: animals; cholesterol; heart rate; inflammation; swine.
Conflict of interest statement
Influence of parasympathetic modulation in doppler mitral inflow velocity in individuals without heart disease.J Am Soc Echocardiogr. 2010 Jul;23(7):762-5. doi: 10.1016/j.echo.2010.04.007. Epub 2010 May 15. J Am Soc Echocardiogr. 2010. PMID: 20472397
Autonomic effects on the spectral analysis of heart rate variability after exercise.Am J Physiol Heart Circ Physiol. 2009 Oct;297(4):H1421-8. doi: 10.1152/ajpheart.00217.2009. Epub 2009 Jul 31. Am J Physiol Heart Circ Physiol. 2009. PMID: 19648255 Free PMC article.
Preference for salt contributes to sympathovagal imbalance in the genesis of prehypertension.Eur J Clin Nutr. 2013 Jun;67(6):586-91. doi: 10.1038/ejcn.2013.64. Epub 2013 Mar 20. Eur J Clin Nutr. 2013. PMID: 23511853
A structured review of panel studies used to investigate associations between ambient air pollution and heart rate variability.Environ Res. 2016 Jul;148:207-247. doi: 10.1016/j.envres.2016.03.013. Epub 2016 Apr 14. Environ Res. 2016. PMID: 27085495 Review.
Targeting the proprotein convertase subtilisin/kexin type 9 for the treatment of dyslipidemia and atherosclerosis.J Am Coll Cardiol. 2013 Oct 15;62(16):1401-8. doi: 10.1016/j.jacc.2013.07.056. Epub 2013 Aug 21. J Am Coll Cardiol. 2013. PMID: 23973703 Review.