Elsevier

American Heart Journal

Volume 156, Issue 4, October 2008, Pages 759.e1-759.e7
American Heart Journal

Clinical Investigation
Coronary Artery Disease
Decreased heart rate variability is associated with higher levels of inflammation in middle-aged men

https://doi.org/10.1016/j.ahj.2008.07.009Get rights and content

Background

Many traditional risk factors for coronary artery disease (CAD) are associated with altered autonomic function. Inflammation may provide a link between risk factors, autonomic dysfunction, and CAD. We examined the association between heart rate variability (HRV), a measure of autonomic function, and inflammation, measured by C-reactive protein (CRP) and interleukin-6 (IL-6).

Methods

We examined 264 middle-aged male twins free of symptomatic CAD. All underwent ambulatory electrocardiogram monitoring and 24-hour ultra low, very low, low, and high-frequency power were calculated using power spectral analysis. C-reactive protein and IL-6 were measured, and risk factors including age, smoking, hypertension, lipids, diabetes, body mass index (BMI), depression, and physical activity were assessed.

Results

Physical activity, BMI, high-density lipoprotein cholesterol, smoking, depression, and hypertension were directly associated with CRP and IL-6 and inversely associated with one or more HRV variables. There was a graded inverse relationship between all HRV parameters (except high frequency) and CRP and IL-6. After adjustment for age, BMI, activity, high-density lipoprotein, smoking, hypertension, depression, and diabetes, ultra low frequency and very low frequency remained significant predictors of CRP (P < .01).

Conclusions

C-reactive protein is associated with decreased HRV, even after controlling for traditional CAD risk factors. Autonomic dysregulation leading to inflammation may represent one pathway through which traditional risk factors promote development of CAD.

Section snippets

Subjects

Twins included in THS were selected from the Vietnam Era Twin Registry, which includes 7,369 middle-aged male-male twin pairs, both of whom served in the United States military during the Vietnam War.24 The THS included 180 monozygotic and dizygotic twin pairs (360 twins), all born between 1946 and 1956. The methods of construction of this sample have been described previously.4, 25 Briefly, the twins were free of a self-reported previous diagnosis of cardiovascular disease based on survey data

Study population

Of the 325 twins free of cardiovascular disease, 264 had ambulatory electrocardiogram data adequate for analysis. Two subjects and their co-twins were excluded due to IL-6 levels above the outlier threshold. The remaining 260 subjects comprise the study population. The mean age was 54 years (range, 47-60). Eight percent had diabetes, 44% hypertension, and 17% were current smokers. Subject characteristics are listed in Table I.

Associations between HRV, inflammatory markers, and clinical factors

Bivariate correlations between HRV, inflammatory markers, and

Discussion

In middle-aged men free of cardiovascular disease, autonomic dysfunction, as demonstrated by decreased HRV, was associated with higher levels of the inflammatory biomarkers CRP and IL-6. Decreased long-term HRV (ULF and VLF) remained an independent predictor of plasma concentration of CRP after adjustment for CAD risk factors associated with both autonomic dysfunction and inflammation.

Conclusions

Markers of inflammation are associated with decreased HRV, even after controlling for clinical CAD risk factors. Autonomic dysregulation leading to inflammation may represent one pathway through which traditional risk factors promote the development of CAD.

References (39)

  • LiaoD. et al.

    Cardiac autonomic function and incident coronary heart disease: a population-based case-cohort study

    Am J Epidemiol

    (1997)
  • TsujiH. et al.

    Impact of reduced heart rate variability on risk for cardiac events: The Framingham Heart Study

    Circulation

    (1996)
  • LibbyP.

    Inflammation in atherosclerosis

    Nature

    (2002)
  • RidkerP.M. et al.

    Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men

    N Engl J Med

    (1997)
  • RidkerP.M. et al.

    Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men

    Circulation

    (2000)
  • BorovikovaL.V. et al.

    Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin

    Nature

    (2000)
  • ChowdharyS. et al.

    Nitric oxide and cardiac autonomic control in humans

    Hypertension

    (2000)
  • MarzP. et al.

    Sympathetic neurons can produce and respond to interleukin 6

    Proc Natl Acad Sci U S A

    (1998)
  • Mohamed-AliV. et al.

    Beta-adrenergic regulation of IL-6 release from adipose tissue: in vivo and in vitro studies

    J Clin Endocrinol Metab

    (2001)
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      Previous studies have reported that the VLF component reflects the activity of the parasympathetic nervous system and endocrine system [41,42]. In several studies, low VLF has been associated with high levels of inflammation such as interleukins and C-reactivated protein [43–45]. Increased C-reactivated protein production during acute exercise decreases HRV components (especially VLF) excluding HF [46].

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    This study received financial support from the National Institutes of Health (Bethesda, MD) (K24HL077506, R01 HL68630, and R01 AG026255), Emory General Clinical Research Center (Atlanta, GA) (MO1-RR00039), and American Heart Association (Dallas, TX) (0245115N). United States Department of Veterans Affairs (Washington, DC) has supported the development and maintenance of the Vietnam Era Twin Registry. Invaluable assistance provided by VA Cooperative Study Program (Washington, DC); Department of Defense (Washington, DC); National Personnel Records Center (Overland, MO), National Archives, and Records Administration (College Park, MD); the Internal Revenue Service (Washington, DC); NIH (Bethesda, MD); National Opinion Research Center (Chicago, IL); National Research Council (Washington, DC), National Academy of Sciences (Washington, DC); and Institute for Survey Research (Washington, DC), Temple University (Philadelphia, PA).

    Ambulatory electrocardiogram analysis software is provided by GE Medical, Milwaukee, WI.

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