Decreased heart rate variability is associated with higher levels of inflammation in middle-aged men.

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.

[1]  P. Ridker,et al.  Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. , 1997, The New England journal of medicine.

[2]  V. Vaccarino,et al.  Depressive Symptoms and Heart Rate Variability: Evidence for a Shared Genetic Substrate in a Study of Twins , 2008, Psychosomatic medicine.

[3]  R. Cohen,et al.  Power spectrum analysis of heart rate fluctuation: a quantitative probe of beat-to-beat cardiovascular control. , 1981, Science.

[4]  S. Humphries,et al.  β-Adrenergic regulation of IL-6 release from adipose tissue: In vivo and in vitro studies , 2001 .

[5]  B. Wallin,et al.  Simultaneous measurements of cardiac noradrenaline spillover and sympathetic outflow to skeletal muscle in humans. , 1992, The Journal of physiology.

[6]  H V Huikuri,et al.  Heart rate variability and progression of coronary atherosclerosis. , 1999, Arteriosclerosis, thrombosis, and vascular biology.

[7]  A. Victor,et al.  Genetic and environmental contributions to plasma C-reactive protein and interleukin-6 levels – a study in twins , 2006, Genes and Immunity.

[8]  J. Fleiss,et al.  RR variability in healthy, middle-aged persons compared with patients with chronic coronary heart disease or recent acute myocardial infarction. , 1995, Circulation.

[9]  K. Tracey,et al.  Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin , 2000, Nature.

[10]  P. Ridker,et al.  Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. , 2000, Circulation.

[11]  J. Dimsdale,et al.  What do plasma and urinary measures of catecholamines tell us about human response to stressors? , 1991, Circulation.

[12]  P. Libby Inflammation in atherosclerosis , 2002, Nature.

[13]  J. Ickovics,et al.  Effects of propranolol on recovery of heart rate variability following acute myocardial infarction and relation to outcome in the Beta-Blocker Heart Attack Trial. , 2003, The American journal of cardiology.

[14]  D L Eckberg,et al.  Mechanisms underlying very-low-frequency RR-interval oscillations in humans. , 1998, Circulation.

[15]  A. Rebuzzi,et al.  Relation of heart rate variability to serum levels of C-reactive protein in patients with unstable angina pectoris. , 2006, The American journal of cardiology.

[16]  V. Athyros,et al.  Heart rate variability after long-term treatment with atorvastatin in hypercholesterolaemic patients with or without coronary artery disease. , 2001, Atherosclerosis.

[17]  S. Rose-John,et al.  Sympathetic neurons can produce and respond to interleukin 6. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[18]  I. Janszky,et al.  Inflammatory markers and heart rate variability in women with coronary heart disease , 2004, Journal of internal medicine.

[19]  N Rifai,et al.  Absence of diurnal variation of C-reactive protein concentrations in healthy human subjects. , 2001, Clinical chemistry.

[20]  T. Ishimitsu,et al.  Effects of smoking cessation on blood pressure and heart rate variability in habitual smokers. , 1999, Hypertension.

[21]  R. Sheldon,et al.  Dissection of long-range heart rate variability: controlled induction of prognostic measures by activity in the laboratory. , 2004, Journal of the American College of Cardiology.

[22]  Edward J Boyko,et al.  The Vietnam Era Twin Registry , 2002, Twin Research.

[23]  P. Stein,et al.  Higher Levels of Inflammation Factors and Greater Insulin Resistance Are Independently Associated with Higher Heart Rate and Lower Heart Rate Variability in Normoglycemic Older Individuals: The Cardiovascular Health Study , 2008, Journal of The American Geriatrics Society.

[24]  H. Hein,et al.  Increased heart rate and reduced heart-rate variability are associated with subclinical inflammation in middle-aged and elderly subjects with no apparent heart disease. , 2004, European heart journal.

[25]  H. Ross,et al.  Nitric oxide and cardiac autonomic control in humans. , 2000, Hypertension.

[26]  M. Wong,et al.  Cardiac implications of increased arterial entry and reversible 24-h central and peripheral norepinephrine levels in melancholia. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[27]  P. Thompson,et al.  The effects of physical activity on serum C-reactive protein and inflammatory markers: a systematic review. , 2005, Journal of the American College of Cardiology.

[28]  R. Sheldon,et al.  Temporally localized contributions to measures of large-scale heart rate variability. , 1998, The American journal of physiology.

[29]  P. Schwartz,et al.  Single cardiac vagal fiber activity, acute myocardial ischemia, and risk for sudden death. , 1991, Circulation research.

[30]  R W Barnes,et al.  Cardiac autonomic function and incident coronary heart disease: a population-based case-cohort study. The ARIC Study. Atherosclerosis Risk in Communities Study. , 1997, American journal of epidemiology.

[31]  J. Fleiss,et al.  Frequency Domain Measures of Heart Period Variability and Mortality After Myocardial Infarction , 1992, Circulation.

[32]  E Länsimies,et al.  Heart rate variability and its determinants in patients with severe or mild essential hypertension. , 2001, Clinical physiology.

[33]  I. Kushner,et al.  Acute-phase proteins and other systemic responses to inflammation. , 1999, The New England journal of medicine.

[34]  P. Wilson,et al.  Adherence to the Mediterranean Diet Is Inversely Associated With Circulating Interleukin-6 Among Middle-Aged Men: A Twin Study , 2008, Circulation.

[35]  M. Kluger,et al.  Beta-adrenoceptor antagonists suppress elevation in body temperature and increase in plasma IL-6 in rats exposed to open field. , 1996, Neuroendocrinology.

[36]  M. Mittleman,et al.  Interleukin‐6 Levels are Inversely Correlated with Heart Rate Variability in Patients with Decompensated Heart Failure , 2001, Journal of cardiovascular electrophysiology.

[37]  I. Antelmi,et al.  Lower heart rate variability is associated with higher serum high-sensitivity C-reactive protein concentration in healthy individuals aged 46 years or more. , 2006, International journal of cardiology.

[38]  D. Levy,et al.  Impact of reduced heart rate variability on risk for cardiac events. The Framingham Heart Study. , 1996, Circulation.